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Use of Base Metals in Buchwald-Hartwig Coupling

Mechanism + Description

Use of base metal complexes to replace Pd – mechanism as for Pd coupling


General comments

In order to replace the high impact metal, Pd, a number of catalyst systems using base metals like Nickel have been reported for B-H amination. Recent advances in the Ullman reaction using Cu in the presence of various ligand has made this metal an attractive alternative to Pd catalysed B-H amination.


Key references

Org. Lett., 2014, 16, 220–223 Development of an Air-Stable Nickel Precatalyst for the Amination of Aryl Chlorides, Sulfamates, Mesylates, and Triflates

Chemistry Letters, 2011, 40, 1036-1038 Monovalent Nickel Complex Bearing a Bulky N-Heterocyclic Carbene Catalyzes Buchwald–Hartwig Amination of Aryl Halides under Mild Conditions

Adv. Synth. Catal., 2010, 352, 1949–1954 Well-Defined Allylnickel Chloride/N-Heterocyclic Carbene [(NHC)Ni(allyl)Cl] Complexes as Highly Active Precatalysts for C-N and C-S Cross-Coupling Reactions

Org. Process Res. Dev., 2015 19 (10), 1327-1355 Nonprecious Metals Catalyzing Hydroamination and C−N Coupling


Relevant scale up examples with Scheme

None located


Green Review

  1. Atom efficiency (by-products Mwt)
    With optimized metal and ligand stoichiometry, catalytic metals and ligands have negligible contribution to the atom/mass intensity. Bi-products are inorganic salts/amine salts/alcohols. In terms of leaving groups Cl
  2. Safety Concerns
    No major concerns around scaling B-H aminations. Lower mol wt alkylphosphines can be highly flammable.
  3. Toxicity and environmental/aquatic impact
    Main concern is around loss of precious metal/ heavy metal catalysts into waste streams. Most precious and heavy metal levels are tightly regulated. The same applies to potential carry through into the API. See next slide for more details. Some Ni salts are sensitizers and carcinogens and listed on the EU SVHC list – this is of less concern for metallic hydrogenation catalysts. Hydrophobic, high mol wt phosphines can be persistent and bioaccumulative and should not be discharged into aqueous waste streams.

    Simple bases like Na/K hydroxides, carbonates, bicarbonates and phosphate are preferred over organic amines and alkoxides. Local regulations may limit concentrations of phosphate that can be discharged in aqueous waste Cs2CO3 is widely used in Suzuki reactions. This should be substituted if possible.
  4. Cost, availability & sustainable feedstocks
    With high catalytic efficiency, this methodology can be an economical way to access aryl/heteroaryl amine compounds. All metal catalysts have a high LCI from mining and refining and would need to be recovered and recycled.
  5. Sustainable implications
    All metals have a high LCA impact from mining and refining operations, so use should be catalytic with efficient recovery and recycle. Pd is most commonly used precious metal for hydrogenation and this is rated at high risk of depletion. No concern for abundant base metals like Ni, Cu etc. If aryl iodides are used, incineration of waste streams could be problematic (iodine content). Limited utility for waste by-products. Iodine is an element at medium to high risk of depletion. High LCA reagent, although it is possible to recover iodide from waste materials.


Updated ICH Guidelines for Metals in API’s

PDE = Permitted daily exposure